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Multi-year enzyme expression in patients with mucopolysaccharidosis type VI after liver-directed gene therapy
Alessandro Rossi1, Roberta Romano1, Simona Fecarotta2
1Department of Translational Medicine, "Federico II" University, 80131 Naples, Italy.
Background:
Mucopolysaccharidosis type VI (MPS VI) is due to a deficiency of the lysosomal enzyme arylsulfatase B (ARSB) that results in multi-organ accumulation of glycosaminoglycans (GAGs). Limitations of current treatments prompted the development of a liver-directed gene therapy clinical trial for MPS VI.
Methods:
We report the long-term follow-up of patients with MPS VI who discontinued enzyme replacement therapy (ERT) and received a single intravenous infusion of high-dose (6 × 1012 genome copies/kg) recombinant adeno-associated virus serotype 8 (AAV8) vector expressing ARSB under the control of a liver-specific promoter (ClinicalTrials.gov: NCT03173521). Primary outcomes were safety and urinary GAG excretion. Secondary outcomes were endurance and respiratory function.
Findings:
Median follow-up time was 45 months (n = 4, three females and one male; age range: 5-10 years). No late-emergent safety events were observed. Patients showed sustained serum ARSB activity (38%-67% of mean healthy reference values), a modest increase in urinary GAG concentrations, and no relevant changes in endurance, cardiac, or pulmonary function. In one of the four patients, ERT was restarted because of elevated urinary GAGs without decreased serum ARSB activity up to about 2.5 years after gene transfer. Liver and spleen size remained within the reference ranges.
Conclusions:
A single intravenous administration of AAV8.TBG.hARSB was safe and resulted in sustained ARSB expression and a modest increase in urinary GAGs in most patients, thus supporting liver-directed gene therapy for MPS VI.
Funding:
This study was sponsored by the Telethon Foundation ETS, the European Union, the Isaac Foundation, and the Italian Ministry of University and Research.
Insights
Liver-directed gene therapy using AAV8 vectors is safe for Mucopolysaccharidosis type VI (MPS VI). This treatment led to sustained enzyme activity and modest GAG reduction in most patients, offering a promising new therapy for MPS VI.
Area of Science:
- Medical Genetics
- Lysosomal Storage Diseases
- Gene Therapy
Background:
- Mucopolysaccharidosis type VI (MPS VI) is a rare genetic disorder caused by arylsulfatase B (ARSB) deficiency, leading to glycosaminoglycan (GAG) accumulation.
- Current treatments for MPS VI have limitations, necessitating the development of novel therapeutic approaches.
- Liver-directed gene therapy presents a potential strategy to address the underlying cause of MPS VI.
Purpose of the Study:
- To evaluate the long-term safety and efficacy of a liver-directed gene therapy in patients with MPS VI.
- To assess the impact of gene therapy on biochemical markers, physical function, and organ size in MPS VI patients.
- To determine the feasibility of using recombinant adeno-associated virus serotype 8 (AAV8) vectors for MPS VI treatment.
Main Methods:
- A single intravenous infusion of a high-dose AAV8 vector encoding ARSB was administered to four MPS VI patients who had discontinued enzyme replacement therapy (ERT).
- The study monitored patients for safety events, urinary GAG excretion, serum ARSB activity, endurance, and respiratory function.
- Follow-up duration was a median of 45 months post-gene therapy administration.
Main Results:
- No late-emergent safety issues were observed in the patients.
- Sustained serum ARSB activity was detected, ranging from 38% to 67% of healthy reference values.
- Most patients exhibited a modest increase in urinary GAG concentrations, with one patient requiring ERT reinitiation.
Conclusions:
- A single dose of AAV8.TBG.hARSB gene therapy is safe and achieves sustained ARSB expression in MPS VI patients.
- The treatment resulted in a modest reduction in GAG levels for most participants.
- Liver-directed gene therapy shows promise as a viable treatment option for MPS VI.
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